Outcome of 125 Children with Chronic Myelogenous Leukemia Who Received Transplants from Unrelated Donors: The Japan Marrow Donor Program

Article Outline

• Abstract
• Introduction
• Patients and Methods
  • Patients
  • Transplantation Procedures and Recipient–Donor HLA Matching
  • Definitions, Data Collection, and Statistical Analysis
• Results
  • Engraftment
  • aGVHD and cGVHD
  • Relapse
  • Survival
    • LFS
    • OS
  • Causes of Death
  • Effects of HLA Compatibility
  • Effect of Cytogenetic Response at Transplantation
  • Effect of Pre-BMT Imatinib Therapy
• Discussion
• Acknowledgments
• References
• Copyright

Because of a small number of patients, only a few studies have addressed the outcome of bone marrow transplantation (BMT) in children with Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML), who receive graft from a volunteer-unrelated donor (VUD), especially after practical application of imatinib mesylate. The outcomes of BMT from a VUD in 125 children with Ph+ CML were retrospectively reviewed. Patients were identified through the Japan Marrow Donor Program as having undergone BMT between 1993 and 2005 and were aged 1-19 years at the time of transplant (median age, 14 years). The probabilities of 5-year overall survival (OS) and leukemia-free survival (LFS) were 59.3% and 55.5%, respectively. Multivariate analysis identified the following unfavorable survival factors: infused total nucleated cell dose<314×10⁶ /kg (relative risk [RR]=2.43; 95% confidence interval [CI]=1.33-4.44; P=.004), advanced phase (RR=2.43; 95% CI=1.37-4.31; P=.004), and no major cytogenetic response (MCyR) at the time of BMT (RR=6.55; 95% CI=1.98-21.6; P=.002). Of the 17 patients treated with imatinib, 15 (88%) achieved MCyR at the time of BMT, and this group had an excellent 5-year OS of 81.9%. Disease phase, infused total nucleated cell dose, and cytogenetic response were independent risk factors for survival of unrelated BMT. These findings provide important information for assessing the indications for and improving outcome in unrelated BMT for the treatment of pediatric CML.

Key Words: Chronic myelogenous leukemia, Children, Unrelated donor, Stem cell transplantation, Bone marrow transplantation, Japan Marrow Donor Program

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Introduction 

Philadelphia-positive (Ph+) chronic myelogenous leukemia (CML) is a rare disease in children, accounting for only 3%-5% of all pediatric leukemia, with a incidence of <1 in 100,000 children [1]. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only proved curative treatment for children with Ph+ CML. Reported event-free survival (EFS) in children with Ph+ CML who underwent transplantation in the chronic phase with a matched related donor is 60%-75% 2, 3, 4; however, this approach is limited by the availability of HLA-matched family donors. The majority of children who lack an HLA-matched donor receive a transplant from an alternative donor, such as a volunteer-unrelated donor (VUD). EFS is less favorable in this setting, ranging from 30% to 55% 3, 4, 5.

Since the introduction of the novel tyrosine kinase inhibitor imatinib mesylate, the treatment for Ph+ CML has been completely revised [6]. Imatinib can induce complete hematologic and cytogenetic remission in the majority of patients, and follow-up data on patients treated only with imatinib indicate that complete cytogenetic and major molecular responses are durable, while drug toxicity is low [7]. The number of transplantations for Ph+ CML has declined rapidly [8]. But, despite significant cytogenetic and molecular responses, there is no evidence that imatinib is curative, and imatinib's long-term side effects remain to be determined. Some patients have successfully stopped imatinib without recurrence, but some who were polymerase chain reaction (PCR)-negative for a period stopped and then experienced recurrence 9, 10. Stopping imatinib may be possible, but effective strategies have yet to be developed.

This is particularly important for pediatric patients, in whom the goal is cure of the disease rather than palliation, and for whom long-term survival is particularly anticipated. The presence of molecular disease and the emergence of resistant clones in patients treated with imatinib suggest the need for caution with regard to abandoning curative therapy by SCT. The need for information on the current status of SCT for Ph+ CML and up-to-date results when considering the treatment of children with Ph+ CML, even in the imatinib era, is evident; however, few studies have specifically analyzed outcomes of SCT in children with Ph+ CML 2, 3, 4, 5. The aim of the present study was to analyze data from 125 children with Ph+ CML who underwent bone marrow transplantation (BMT) from a VUD and identify factors influencing outcome.

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Patients and Methods 

Patients 

A retrospective analysis was conducted on behalf of the Japan Marrow Donor Program (JMDP) and the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) CML Committee. Data were collected from 125 children (age at transplantation<20 years) whose donors were identified through the JMDP and who underwent allogeneic BMT from a VUD for Ph+ CML between 1993 and 2005. Table 1 summarizes the patient, donor, and transplant characteristics. Patient characteristics in the first chronic phase (CP1) and in the advanced phase are described separately. All patients or their guardians gave written informed consent for transplantation and submission of data to the JMDP for further research. This study was approved by the Data Management Committee of the JMDP and by the Ethical Committee of Nagoya University Graduate School of Medicine.

Table 1. Patient, Donor, and Transplant Characteristics

	CP1 (n=88)	Advanced Phase (n=37)	Total (n=125)
Year of transplantation
1993-1998	45	22	67
1999-2005	43	15	58
Stage of CML at BMT
CP1	88	0	88
CP2	0	12	12
CP3	0	1	1
Advance phase	0	11	11
Blast crisis	0	13	13
Cytogenetic response at BMT
With MCyR	29	4	33
Without MCyR	39	25	64
Unknown	20	8	28
Pretransplantation therapy with IFN-α
No	22	8	30
Yes	66	29	95
Pretransplantation therapy with imatinib
No	72	36	108
Yes	16	1	17
Recipient sex, M/F	56/32	25/12	81/44
Donor–recipient sex
Female donor to male recipient	20	10	30
Other	68	27	95
Median age at BMT, years (range)	13 (1-19)	17 (2 -19)	14 (1-19)
Median time from diagnosis to transplantation, months (range)	14 (2-111)	19 (5-103)	14 (2-111)
Patient CMV antibody
Negative	25	14	39
Positive	54	21	75
Unknown	9	2	11
ABO mismatch
Match	41	15	56
Major mismatch	29	11	40
Minor mismatch	17	9	26
Unknown	1	2	3
Recipient–donor HLA DNA typing
Match (10/10)	33	8	41
1 alleles mismatch	9	5	14
2 alleles mismatch	19	9	28
3 alleles mismatch	8	3	11
4 alleles mismatch	2	2	4
6 alleles mismatch	0	1	1
Unknown	17	9	26
Conditioning regimen
TBI regimen	66	30	96
Non-TBI regimen	22	7	29
GVHD prophylaxis
CsA+MTX	59	22	81
Tacrolimus+MTX	28	15	43
MTX alone	1	0	1
Administration of ATG
No	76	34	110
Yes	12	3	15
Median infused total nucleated cell dose, × 106 /kg (range)	315 (27-880)	298.5 (29-750)	314 (27-880)

ATG indicates antithymocyte globulin; BMT, bone marrow transplantation; CML, chronic myelogenous leukemia; CP, chronic phase; CMV, cytomegalovirus; CsA, cyclosporine; IFN, interferon; GVHD, graft-versus-host disease; MCyR, major cytogenetic response; MTX, methotrexate; TBI, total body irradiation.

The 125 children in the study included 81 boys (65%) and 44 girls (35%). The median age at the time of BMT was 14 years (range, 1-19 years). Disease phase at the time of transplantation was defined according to International Bone Marrow Transplant Registry (IBMTR) criteria [11]. Eighty-eight patients (70%) underwent transplantation in CP1. Of the 37 children who underwent transplantation in an advanced phase of CML, 12 were in CP2, 1 was in CP3, 11 were in the accelerated phase (AP), and 13 were in blast crisis (BC). Cytogenetic response data at the time of BMT were available for 97 patients (78%), of whom 68 were in CP1 and 29 were in an advanced phase. Major cytogenetic response (MCyR; ≤ 35% Ph+ cells) was achieved in 33 patients (29 patients in CP1 and 4 patients in CP2). Ninety-five recipients (76%) were given interferon (IFN)-α, and 17 (14%) were given imatinib before transplantation. The patients treated with imatinib proceeded to BMT regardless of their response, according to each institutes' therapeutic strategy. The median interval from diagnosis to transplantation was 14 months (range, 2-111 months). Fifty-seven patients (46%) underwent transplantation within 12 months, and 68 (54%) did so after 12 months. Imatinib began to be used in Japan in 1999, and its use was approved by the Japanese Health and Welfare Ministry in 2002. In our cohort, 17 patients (16 in CP1, 1 in AP) received imatinib before transplantation.

Transplantation Procedures and Recipient–Donor HLA Matching 

All 125 recipients received a BM graft from a VUD identified through the JMDP. Various preconditioning regimens were used by individual centers. Of the 125 recipients, 96 (77%) received a preparative regimen with total body irradiation (TBI). Fifteen recipients (12%) received antithymocyte globulin (ATG). Cyclosporine A (CsA)–based GVHD prophylaxis was used in 81 patients (65%); tacrolimus-based prophylaxis, in 43 (34%). One patient received only methotrexate (MTX) as GVHD prophylaxis. HLA-matching data based on high-resolution DNA typing for HLA-A, -B, -C, -DRB1, and -DQB1 antigens were available in 99 patients (79%). Of these 99 patients, 41 (41%) were fully matched at 10/10 alleles, 14 (14%) were mismatched at 1 HLA allele, 28 (28%) were mismatched at 2 HLA alleles, and 16 (16%) were mismatched at more than 3 HLA alleles.

Definitions, Data Collection, and Statistical Analysis 

The outcomes were analyzed on the basis of engraftment, grade II-IV acute and chronic GVHD (aGVHD, cGVHD), treatment-related mortality (TRM), relapse, overall survival (OS), and leukemia-free survival (LFS). The date of engraftment was defined as the first of 3 consecutive days with a neutrophil count exceeding 0.5×10⁹ /L. aGVHD and cGVHD were classified according to published criteria [12]. Only patients surviving for >100 days after transplantation were considered eligible for evaluation of cGVHD. Relapse of CML was defined by hematologic or cytogenetic evidence of disease. (Data on molecular evidence of relapse were not available.) Transplantation data were collected using standardized forms provided by the JMDP. After transplantation, patient baseline information and follow-up reports were submitted at 100 days, 6 months, 1 year, and annually thereafter.

Comparisons between groups were performed using Fisher's exact test for categorical variables and the Mann-Whitney U test for continuous variables. Survival and time to events were calculated from the date of transplantation. OS and LFS were estimated by the Kaplan-Meier method and compared using the log-rank test. Cumulative incidence curves were created for TRM. The Cox proportional hazard model was used to obtain the estimates and the 95% confidence interval (CI) of the relative risk (RR) for predictive factors and to evaluate predictive factors for TRM, LFS, and OS in a multivariate analysis. The following variables were evaluated: patient age at the time of BMT (≥ 15/< 15 years), patient sex, sex mismatch, year of transplantation (1993-1998/1999-2005), period from diagnosis to transplantation (≥ 12 months/< 12 months), infused total nucleated cell dose (≥ 314×10⁶/kg/< 314×10⁶/kg), TBI-containing regimen (yes/no), use of ATG (yes/no), GVHD prophylaxis (CsA + MTX ± steroids/FK±MTX), full HLA matching (yes/no), disease phase at the time of BMT (CP1/advanced phase), MCyR at the time of BMT (yes/no), ABO mismatch (match/mismatch), recipient cytomegalovirus (CMV) antibody (negative/positive), history of interferon therapy (yes/no), and history of imatinib therapy (yes/no). Variables with more than 2 categories were dichotomized for the final multivariate model. The cutoff points of the variables were chosen to make optimal use of the information, with the proviso that smaller groups contained at least 20% of the patients. The cutoff points of continuous variables were chosen from the 25th, 50th, and 75th percentiles; consequently, the median of continuous variables was dichotomized as follows: age (≥15/< 15 years), year of transplantation (1993-1998/1999-2005), and infused total nucleated cell dose (≥ 314×10⁶/kg/< 314×10⁶/kg). SPSS version 15.0 (SPSS Inc, Chicago, IL) was used for all statistical calculations except estimation of the cumulative incidence, which was performed using Stata version 10.0 (StataCorp, College Station, TX).

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Results 

Engraftment 

A total of 119 recipients (95%) were successfully engrafted. Neutrophil engraftment occurred at a median of 18 days after BMT (range, 11-37 days). Six patients (5%) experienced primary graft failure (Table 2), all of whom died.

Table 2. Patient Clinical Outcomes

	CP1 (n=88)	Advanced Phase (n=37)	Total (n=125)	P Value
Engraftment				.336
Yes/No	85 / 3	34 / 3	119 / 6
Acute GVHD				.186
None	21	11	32
Grade I	34	9	43
Grade II	18	5	23
Grade III	11	7	18
Grade IV	4	5	9
Chronic GVHD				.393
None	49	25	74
Limited	15	6	21
Extensive	24	6	30
5-year TRM (95% CI)	28.3% (23.4-33.2)	56.5% (48.0-65.0)	36.5% (32.5-40.5)	.002
5-year relapse rate (95% CI)	11.8% (8.1-15.5)	29.0% (18.7-39.3)	15.4% (11.7-19.1)	.098
5-year LFS (95% CI)	65.2% (60.0-70.4)	32.4% (24.7-40.1)	55.5% (51.0-60.0)	.001
5-year OS (95% CI)	70.7% (65.7-75.7)	32.4% (24.7-40.1)	59.3% (54.8-63.8)	<.001

GVHD indicates graft-versus-host disease; LFS, leukemia-free survival; OS, overall survival; TRM, treatment-related mortality.

aGVHD and cGVHD 

Grade II-IV aGVHD occurred in 50 patients (40.7%; 95% CI=36.3%-45.1%), and grade III-IV aGVHD occurred in 27 patients (22.6%; 95% CI=16.1%-31.2%). Fifty-one patients (50.1%; 95% CI=45.0%-55.2%) developed cGVHD (extensive type, n=30; limited type, n=21).

Relapse 

Seventeen patients (11 recipients in CP1 and 6 in an advanced phase) experienced a relapse. The 5-year cumulative incidence of relapse was 19.7% (95% CI=15.1%-24.3%). The median time for occurrence of relapse for the entire study cohort was 7 months (range, 1-97 months).

Survival 

The 5-year LFS rate was 55.5% (95% CI=51.0%-60.0%) for the entire cohort (Figure1). The LFS rate was significantly higher in children undergoing BMT in CP1 (65.2%; 95% CI=60.0%-70.4%) than those undergoing BMT in an advanced phase (32.4%; 95% CI=28.7%-36.1%; P=.001) (Table 2).

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• Figure 1 

  OS and LFS in children with Ph+ CML. In Kaplan-Meier curves graph, solid line shows the probabilities of OS (5-year OS=59.3%; 95% CI=54.8%-63.8%) and the dotted line shows that of LFS (5-year LFS=55.5%; 95% CI=51.0%-60.0%).

On univariate analysis, the following factors were significantly associated with LFS: age at the time of BMT (P=.047), infused total nucleated cell dose (P=.002), disease phase (P=.002), and cytogenetic response at the time of BMT (P=.001). Multivariate analysis also identified infused total nucleated cell dose (RR=2.320; 95% CI=1.326-4.061; P=.003), disease phase (RR=2.051; 95% CI=1.187-3.545; P=.010), and cytogenetic response at the time of BMT (RR=2.890; 95% CI=1.264-610); P=.012) as independent risk factors for LFS.

The 5-year OS rate was 59.3% (95% CI=54.8%-63.8%) for the entire cohort (Figure 1). The OS rate was significantly higher in the children undergoing BMT in CP1 (70.7%; 95% CI=65.7%-75.7%) than in those undergoing BMT in an advanced phase (32.4%; 95% CI=24.7%-40.1%; P < .001) (Table 2).

On univariate analysis, the following risk factors were significantly associated with OS: age at the time of BMT (P=.037), interval between diagnosis and BMT (P=.042), infused total nucleated cell dose (P=.002), disease status (P <.001), and cytogenetic response at the time of BMT (P=.002). A history of imatinib therapy before BMT marginally affected OS (P=.099). Multivariate analysis identified infused total nucleated cell dose (RR=2.426; 95% CI=1.326-4.441; P=.001) (Figure 2A), disease status (RR=2.427; 95% CI=1.368-4.305; P=.002), and cytogenetic response at the time of BMT (RR=6.547; 95% CI=1.982-21.629; P=.002) (Figure 2C) as independent risk factors for OS (Table 3).

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• Figure 2 

  A and B, Relationship among infused total nucleated cell dose, OS (A), and TRM (B) in children with Ph+ CML. In the entire cohort, OS was significantly higher for children who received a higher infused total nucleated cell dose than those who received a lower dose (≥ 314×10⁶/kg vs<314×10⁶/kg; P=.001). TRM was significantly higher for children who received a lower cell dose than for those who received a higher cell dose (≥ 314×10⁶/kg vs<314×10⁶/kg; P=.003). Solid lines show the probabilities of OS and TRM for children who received a higher infused total nucleated cell dose and the dotted lines show the probabilities for those who received a lower infused total nucleated cell dose. C and D, OS (C) and TRM (D) of Ph+ CML children in CP1 with or without an MCyR. OS was significantly higher for children who achieved MCyR at the time of BMT (n=29) than for those who did not (n=39) (OS; P < .001) (C). TRM was also significantly higher for children who did not achieve MCyR (P=.005) (D). The solid lines show the probabilities of OS and TRM for children with MCyR at the time of BMT, and the dotted lines show the probabilities for those without.

Table 3. Risk Factors for TRM and OS on Multivariate Analysis

Covariates	RR (95% CI)	P value
TRM
Infused cell dose
≥314×106/kg	(1)
<314×106/kg	2.347 (1.195-4.610)	.013
Cytogenetic response at BMT
With MCyR	(1)
Without MCyR	9.055 (2.151-38.127)	.003
OS
Infused total nucleated cell dose
≥314×106/kg	(1)
<314×106/kg	2.426 (1.326-4.441)	.004
Disease phase at BMT
CP1	(1)
Advanced phase	2.427 (1.368-4.305)	.002
Cytogenetic response at BMT
With MCyR	(1)
Without MCyR	6.547 (1.982-21.629)	.002

BMT indicates bone marrow transplantation; MCyR, major cytogenetic response; OS, overall survival; TRM, treatment-related mortality.

Causes of Death 

Fifty-two patients (42%) died after BMT from a VUD (Table 4). The day-100 mortality rate was 15.2 % (95% CI=12.0%-18.4%). The main cause of death was transplantation-related complications, from which 46 patients (37%) died between day 8 and 10 years (median, 4 months) after transplantation. These included 18 transplantation-related deaths occurring before day 100 after transplantation. Death was associated with treatment-resistant GVHD in 14 patients (9 with aGVHD and 5 with cGVHD). Infection was the cause of death in 12 patients. Six patients died from recurrent CML between 3 and 28 months (median, 13 months) after transplantation.

Table 4. Causes of Death

	CP1 (n=88)	Advanced Phase (n=37)	Total (n=125)
TRM	26	20	46
Infections
Bacterial	4	1	5
Fungal	1	0	1
Viral	3	1	4
Pneumocystis jirovecii	1	0	1
Unknown	0	1	1
Rejection	0	1	1
Acute GVHD	5	4	9
Chronic GVHD	4	1	5
Idiopathic interstitial pneumonitis	6	4	10
Cardiac failure	0	1	1
Respiratory failure	0	1	1
Renal failure	1	1	2
Hemorrhage	0	2	2
Secondary malignancy	1	0	1
Unknown	0	2	2
Relapse	1	5	6

CP indicates chronic phase; GVHD, graft-versus-host disease; TRM, treatment-related mortality.

Univariate analysis revealed that infused cell dose (P=.013), disease phase (P=.006), and cytogenetic response at the time of BMT (P=.001) were significant risk factors for TRM. The interval between diagnosis to BMT (P=.083) and HLA mismatch (P=.087) were marginally associated with TRM. In the multivariate model, infused cell dose (RR=2.347; 95% CI=1.195-4.610; P=.013) (Figure 2B) and cytogenetic response at the time of BMT (RR=9.055; 95% CI=2.151-38.127; P=.003) (Figure 2D) were independent risk factors for TRM (Table 3).

Effects of HLA Compatibility 

The influence of HLA compatibility between recipient and donor on aGVHD, TRM, and OS was assessed by univariate analysis. aGVHD (grade II-IV) was less frequent in patients with fully matched donors than in those with mismatched donors (RR=2.044; 95% CI=1.055-3.961; P =.034). TRM (RR=1.902; 95% CI=0.894-4.045; P =.095) and OS (RR=1.572; 95% CI=0.817-3.027; P =.176) tended to be worse in mismatched transplantation, but the difference was not statistically significant. In the analysis of each single allele mismatch, only the HLA-A allele mismatch significantly affected OS (RR=2.837; 95% CI=1.347-5.977; P =.006). HLA-C mismatch marginally affected OS (RR=1.639; 95% CI=0.945-2.843; P =.078), whereas HLA-B, -DRB1, and -DQB1 mismatch were not significant. On multivariate analysis, HLA compatibility was not identified as an independent risk factor for acute GVHD, TRM, or OS.

Effect of Cytogenetic Response at Transplantation 

Cytogenetic response data were available in 68 of 88 patients (77%) who underwent transplantation in CP1. Sixteen patients received imatinib, 35 received IFN-α, and 3 received neither imatinib nor IFN-α. MCyR at the time of BMT was achieved in 15 of the 16 patients (94%) treated with imatinib and in 14 of the 35 patients (40%) treated with IFN-α.

Patients with MCyR at the time of BMT (n=29) had significantly better OS and LFS than those without MCyR (n=39): 5-year OS=91.4%, 95% CI=85.4%-97.4% versus 53.4% and 45.3%-61.5% (P=.001); 5-year LFS=81.0 %, 95% CI=73.2%-88.8% versus 50.9% and 42.8%-59.0% (P=.02) (Figure 2C). Although no significant difference in relapse rate was seen between the 2 patient groups (P=.91), TRM was significantly lower in those who achieved MCyR at the time of BMT (n=29) than in those who did not (n=39): 5-year TRM=9.6 %, 95% CI=3.0%-16.2% vs 41.0% and 32.7%-49.3% (P=.005) (Figure 2D).

Effect of Pre-BMT Imatinib Therapy 

In this cohort, 17 patients received imatinib before transplantation, and 15 of them (88.2%) achieved MCyR in CP1 before transplantation. This percentage was significantly higher than that in the patients who did not receive imatinib (88.2% vs 22.2%; P < .01). A history of imatinib therapy had a positive effect on survival (5-year OS=81.9 %, 95% CI=72.4%-91.4% vs 56.4% and 51.6%-61.2%; P=.086), but this effect was not statistically significant.

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Discussion 

Because of the small number of patients, to date only a few studies have addressed the outcome of children with Ph+ CML undergoing BMT with a VUD 3, 4, 5. The number of patients in the present study is comparable to that of the largest previous study, which included 132 children with CML undergoing BMT from a VUD [4]. Furthermore, unlike that previous study, our data set contains detailed information on infused total nucleated cell dose, high-resolution HLA compatibility, and cytogenetic response at the time of BMT. Until now, these variables have not been evaluated in a pediatric CML population.

In clinical settings 13, 14, 15, as well as in animal models 16, 17, larger cell dose is recognized as an important predictor of a favorable outcome for allogeneic BMT. When an adult patient with CML receives a transplant from a VUD, a lower infused total nucleated cell dose is associated with an increased incidence of TRM [18]. Our findings also demonstrate an association between lower infused total nucleated cell dose and lower OS and LFS and a higher incidence of TRM. These correlations are independent of recipients' age. Moreover, all 6 patients who experienced graft failure were in the lower infused total nucleated cell dose group. Based on our findings, we recommend BM harvest teams attempt to collect a higher number of nucleated cells for infusion in CML patients undergoing BMT from a VUD.

Cytogenetic response to previous treatment with IFN-α [19] and imatinib [20] has been reported to be predictive for survival after allogeneic SCT in Ph+ CML. In the multivariate model of our entire cohort, MCyR at the time of BMT was an independent predictive factor for transplantation outcome. Furthermore, subgroup analysis of the patients in CP1 confirmed that the lower TRM rate in patients with MCyR at the time of BMT contributed to a better survival rate (Figure 2C), suggesting that MCyR is important for better transplantation outcome in CP1 CML as well. Recently, the Center for International Blood and Bone Marrow Transplant Research reported a significantly lower TRM and a better OS in imatinib-treated patients undergoing allogeneic SCT [21]. In our cohort, the imatinib-treated patients tended to have a higher OS (P=.086), but the difference was not statistically significant; however, our imatinib-treated group was small (17 of 125 patients), which may have reduced the statistical power.

We have now multiple treatment modalities for pediatric CML, including allogeneic SCT, imatinib, and, more recently, second-generation tyrosine kinase inhibitors. Although only few small studies have analyzed the data on pediatric imatinib monotherapy 22, 23, those studies have reported comparable results to adult large clinical trials 24, 25, 26. Growth disturbance as a side effect of imatinib in a pediatric CML patient was reported recently [27]; this effect could be a serious drawback to long-term imatinib therapy in the future. Of course, allogeneic SCT also has potential long-term sequelae, including growth retardation. We are currently planning a study comparing the long-term outcomes and complications of therapy with tyrosine kinase inhibitors and allogeneic SCT in the imatinib era.

In summary, disease phase, infused total nucleated cell dose, and cytogenetic response at the time of BMT were found to be independent risk factors for OS, LFS, and TRM in BMT from a VUD for the treatment of pediatric CML. These results provide important information for evaluating indications and improving outcome in children with CML undergoing unrelated BMT.

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Acknowledgments 

Financial disclosure: The authors have nothing to disclose.

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